Examples of known methods for the synthesis of (R)-4-cyano-3-hydroxybutyric acid esters include a method in which arabinose or ascorbic acid as an asymmetric reactant is converted to methyl (S)-4-bromo-3-hydroxybutyrate and then the hydroxyl group is protected with a protecting group (e.g., tetrahydropyrranyl, a trialkylsilyl, an alkyl or the like) prior to reaction with sodium cyanamide (Acta Chem. Scand., B37, 341 (1983)); a method in which threonine calcium salt monohydrate, obtained by allowing L-ascorbic acid to react with hydrogen peroxide and calcium carbonate is allowed to react with hydrogen bromide to provide its dibromo form which is then converted to bromohydrin, subsequently protecting the hydroxyl group with the aforementioned protecting group and then carrying out reaction with sodium cyanamide (Carbohydrate Res., 72, 301 (1979)); a method in which 4-chloro-3-hydroxybutyronitrile is hydrolyzed to the carboxylic acid which is then subjected to ethylesterification and subsequent reaction with potassium cyanate (Bull. Chem. Soc. Fr., 33, 732 (1923)); a method in which a 4-halogeno-acetoacetic acid alkyl ester obtained from diketene is subjected to asymmetric reduction reaction using a ruthenium-optically active phosphine complex to convert it into t-butyl (S)-4-halogeno-3-hydroxybutyrate (JP-A-1-211551; the term "JP-A" as used herein means an "unexamined published Japanese patent application), and subsequently carrying out a cyano-introducing reaction (JP-A-5-331128); and a method in which ethyl (S)-4-bromo-3-hydroxybutyrate is allowed to react directly with sodium cyanamide (a national phase published Japanese patent application No. 7-500105).
Of these five reported methods, the first three methods cannot be considered practical industrial production methods due to the necessity for attaching and detaching a protecting group to and from the hydroxyl group and for carrying out separation of the optically active substance. Also, when the (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester is synthesized in the case of the last two methods, reaction yield of the cyano-introducing reaction is 57% at most and a relatively large amount of the (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester used as the starting material remains un-reacted. In addition, in order to isolate a high purity (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester from the reaction mixture, purification by vacuum distillation has generally been carried out after extraction with an appropriate solvent.
It has now been discovered herein that this type of vacuum distillation results in a low product yield unless the distillation is carried out under extremely low temperature and low pressure conditions. That is, thermal decomposition of the (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester generates water, hydrogen chloride and the like which accelerate decomposition of the corresponding (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester. Significant thermal decomposition of (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester can be observed at a temperature of 120.degree. C. or more and is so drastic that the entire ester will eventually decompose, for example, after several hours at 150.degree. C. Therefore, it is essential to operate the distillation step at a temperature as low as possible, particularly at the time of the initial distillation, for distilling (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester in order to prevent decomposition of the (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester. Even then, some quantity of decomposition is unavoidable, and, in the worst case, there is a possibility that the decomposition may cause such a reduction in operating pressure and increase in temperature as to worsen the problem of further thermal decomposition. In addition, the (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester product is obtained at high production cost, because not only is it an expensive material but its decomposition product cannot be recovered. The present invention provides a method which can overcome all of these problems.